Neurologia i Neurochirurgia Polska 2012; 46, 2

140

Correspondence address: Izabela Domitrz, Department of Neurology, Medical University, 1A Banacha Street, 02-097 Warsaw, Poland,
phone: [phone], fax: [phone], e-mail: [e-mail]
Received: 24.09.2011; accepted: 15.12.2011

A b s t r a c t

Background and purpose: Mutations of CACNA1A, which
encodes a neuronal P/Q Ca

2+

channel, are present in patients

with familial hemiplegic migraine, and possibly in other types
of migraine as well. This calcium channel is also involved in
neuromuscular transmission. In our previous study we con-
firmed that the single-fibre electromyography (SFEMG)
method can demonstrate a neuromuscular transmission deficit
in migraine with aura. The aim of our present study was to
estimate the neurotransmitter dysfunction in cluster headache
and to compare the results between patients with cluster head -
ache and those with migraine with aura.
Material and methods: We selected 6 patients with cluster
headache and 6 patients with migraine with typical aura.
SFEMG of the voluntarily activated extensor digitorum com-
munis muscle was performed.
Results: The SFEMG results were in the normal range in
the cluster headache group and in the healthy controls. Slight
neuromuscular transmission disturbances were present in
patients with migraine with aura.
Conclusions: The abnormal neuromuscular transmission
detectable by SFEMG may reflect a genetically determined
dysfunction of the P/Q Ca

2+

channels in a group of mi grai -

neurs with aura. Conversely, absence of neuromuscular abnor-
malities in cluster headache patients could be explained by
different aetiology not resulting in channelopathy. Single-fibre

A single-fibre electromyography study of neuromuscular transmission in patients
with cluster headache

Elektromiografia pojedynczego w³ókna u chorych na klasterowy ból g³owy

Izabela Domitrz

1

, Ma³gorzata Gawe³

1

, Wojciech Domitrz

2

, Anna Kostera-Pruszczyk

1

, Hubert Kwieciñski

1

1

Department of Neurology, Medical University of Warsaw, Poland

2

Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland

Neurologia i Neurochirurgia Polska 2012; 46, 2: 140-144
DOI: 10.5114/ninp.2012.28256

ORIGINAL PAPER/

ARTYKU£ ORYGINALNY

S t r e s z c z e n i e

Wstêp i cel pracy: U chorych na migrenê rodzinn¹ po³owi-
czoporaŸn¹, a tak¿e z innymi postaciami migreny z aur¹
stwierdzono mutacjê w genie CACNA1A dla kana³u wapnio-
wego P/Q. Z uszkodzeniem tego kana³u wapniowego zwi¹ -
zane s¹ zaburzenia przewodzenia nerwowo-miêœniowego.
We wczeœniejszej pracy autorzy opisali badanie za pomoc¹
elektromiografii pojedynczego w³ókna (SFEMG) zaburzeñ
przewodzenia nerwowo-miêœniowego u osób z migren¹,
stwierdzaj¹c ich obecnoœæ u czêœci pacjentów z migren¹
z aur¹. Celem niniejszego badania jest odpowiedŸ na pytanie,
czy u pacjentów z klasterowym bólem g³owy wystêpuj¹ po -
dobne zaburzenia, i porównanie wyników otrzymanych u osób
z klasterowym bólem g³owy z wynikami pacjentów z migren¹
z aur¹.
Materia³ i metody: Elektromiografiê pojedynczego w³ókna
wykonan¹ z miêœnia zginacza d³ugiego palców przeprowa-
dzono u 6 pacjentów z klasterowym bólem g³owy i zestawio-
no j¹ z wynikami 6 chorych na migrenê z aur¹.
Wyniki: Wyniki SFEMG w grupie chorych na klasterowy
ból g³owy mieœci³y siê w prawid³owych granicach, podobnie
jak w grupie kontrolnej zdrowych osób. W grupie pacjentów
z migren¹ z aur¹ stwierdzono ³agodne zaburzenia transmisji
nerwowo-miêœniowej.
Wnioski: Nieprawid³owe wyniki SFEMG mog¹ wskazywaæ
na genetycznie uwarunkowan¹ dysfunkcjê kana³u wapniowe go

Neurologia i Neurochirurgia Polska 2012; 46, 2

141

Introduction

In our previous study, we demonstrated that single-

fibre electromyography (SFEMG) can reveal mild neu-
romuscular transmission deficit in patients with migraine
with aura [1]. Abnormal neuromuscular transmission
in patients with cluster headache was also reported [2,3].

Although the patients with migraine or cluster head -

ache do not have clinical symptoms of neuromuscular
transmission defect, SFEMG abnormalities may sug-
gest a dysfunction of P/Q Ca

2+

channels. Mutations

of the CACNA1A gene (chromosome 19p13) were first
described in patients with episodic ataxia type 2 and
spinocerebellar ataxia type 6 [4]. In addition, it has
also been demonstrated that CACNA1A mutations are
present in about 50% of families with hemiplegic
migraine [4-6]. In a single report by Baslo et al. [7]
subclinical neuronal muscular transmission (NMT)
abnormality was found in sporadic hemiplegic migraine
and basilar type migraine patients.

We aimed to look for subclinical impairment of

NMT as a possible indicator of underlying ion chan-
nelopathy in cluster headache patients.

Material and methods

We studied a group of six patients with cluster

headache, six patients with migraine with typical aura
and six healthy age-matched controls.

Cluster headache and migraine with aura were diag-

nosed according to the International Headache Society
criteria, 2

nd

edition [8].

The cluster headache group consisted of 6 patients:

2 women and 4 men at a mean age of 43.5 ± 8.7 years.
The migraine with aura group (IHS code 1.2.1) con-
sisted of 6 women at a mean age of 41.5 ± 12.6 years.
All patients with migraine with aura had attacks of
migraine with typical aura. None of the migraine with

aura or cluster headache patients suffered from other
coexisting headaches or other disorders. The control
group consisted of 6 healthy women (mean age of 42.5
± 9.7 years).

The study protocol was approved by the local ethics

committee and the study was conducted with the in -
formed consent of all subjects.

The SFEMG examination was conducted by an

investigator blinded to the clinical diagnosis of the
patient. Single-fibre electromyography of the volun-
tarily activated extensor digitorum communis muscle
was conducted as described by Stalberg et al. [9,10],
using a Keypoint electromyograph (Medtronic, Skov -
lunde, Denmark). In all tested subjects, 20 potential
pairs were collected, and the mean consecutive differ-
ence (MCD) – jitter – value was subsequently calcu-
lated for each pair. The MCD is the mean of the dif-
ferences between the intervals between consecutive
potential pairs, calculated by the software, and is
a standard parameter for assessment of NMT, reflect-
ing the safety factor of the neuromuscular junction
[11]. The mean MCD value and the number of po -
tential pairs with an MCD exceeding 55 μs or block-
ing were noted [12].

The results were compared with our laboratory ref-

erence values and considered abnormal when the mean
MCD value exceeded 33.8 μs, or more than 10% of
pairs had an MCD value above 55 μs with or without
blocking.

All patients were examined interictally, at least three

weeks after the last episode of headache. The patients
were not receiving any drugs for a period of 3 weeks
before the SFEMG examination. Because cluster head -
ache is presumed to activate the trigemino-vascular sys-
tem, we additionally tested the blink reflex in three
women with cluster headache (age range 39-69; mean
50.6). The blink reflex was elicited with electrical stim-
ulation of the left and right supraorbital nerve with an
early, ipsilateral R1 and a late, bilateral R2 response.

electromyography could be a helpful tool in clinically ques-
tionable cases in differentiating between cluster headache and
migraine with aura.

Key words: cluster headache, migraine with aura, P/Q Ca

2+

channels, single-fibre electromyography, neuromuscular trans-
mission.

w grupie chorych na migrenê z aur¹ w przeciwieñstwie do
chorych na klasterowy ból g³owy, u których najprawdopo-
dobniej etiologia choroby ma inne pod³o¿e. Badanie SFEMG
mo¿e byæ badaniem pomocniczym w ró¿nicowaniu niepew-
nych przypadków klasterowego bólu g³owy imituj¹cych
migrenowy ból g³owy.

S³owa kluczowe: klasterowy ból g³owy, migrena z aur¹, kana³y
wapniowe P/Q, zaburzenia transmisji nerwowo-miêœniowej,
elektromiografia pojedynczego w³ókna.

SFEMG in patients with cluster headache

Neurologia i Neurochirurgia Polska 2012; 46, 2

142

Electrical stimulation of supraorbital nerves was per-
formed with a peripheral nerve stimulator and silver/sil-
ver chloride disc surface electrodes.

The results were expressed as means and standard

deviations for quantitative variables and as proportions
for binary data. Means in each group were compared
by one-way analysis of variance. Significance of differ-
ence between pairs of groups and the correlation between
values were checked by t-tests. Statistical calculations
were carried out using Statistica software with p < 0.05
taken as a cut-off value.

Results

The SFEMG results are presented in Table 1 and

Fig. 1. The results (mean MCD) were within the nor-
mal range in the patients with cluster headache and in
the control group. Only in one cluster headache case
(1/6, 16.6%) did the examination reveal borderline dys-
function of neurotransmission. There was no significant
difference between the results of jitter values in patients
with cluster headache compared to controls. Mild
NMT impairment was found in some of the patients
with migraine with aura. All patients showing NMT

impairment had only slight SFEMG abnormalities,
with mean MCD values just above the upper limit of
normal. Pairs of potentials with an MCD above 55 μs
were recorded in patients with migraine with aura,
but no blocking was observed. The individual MCD
values were shifted towards the upper limit of normal
for a single potential pair in each case. Although there
was a signi ficant difference of the mean MCD between
the control group and patients with migraine with aura
(p = 0.003), no such difference was demonstrated
between the cluster headache group and healthy con-
trols (p = 0.24) or between the group of patients with
cluster headache and the migraine with aura group
(p = 0.38). There was no correlation between age and
onset of disease and jitter results in study groups.

Blink reflex examination revealed normal latencies

and amplitudes of R1 and R2 responses in all three
patients with cluster headache.

Discussion

Our study did not reveal subclinical impairment of

NMT in cluster headache patients in contrast to mild
dysfunction in a subgroup of patients with migraine with
aura, as observed previously by other authors [13-15].
To date only a small number of studies have analysed
SFEMG in cluster headaches. Ertas et al. [3] suggest-
ed that episodic cluster headache might share the same
abnormality of neuromuscular transmission observed in
migraine. They found subclinical abnormality in jitter
results in 3 of 6 patients with cluster headache [3]. In
a sub sequent study, Coban et al. [2] demonstrated that
the subclinical NMT abnormality shown by SFEMG
was more common in cluster headache (21.6%) than in
MA (11.6%).

In migraines with aura, NMT dysfunction could be

explained by underlying genetic factors inducing a Ca
channelopathy which accounts for both the headache
phenotype and transmission abnormalities, but there is
no such suggestion in cluster headache. The aetiology

Group

Cluster headache (

n = 6) Migraine with aura (n = 6)

Control group (

n = 6)

MCD [μs], mean ± SD (range)

30 ± 5.8 (24-40)

32 ± 2.9 (28-36)

27 ± 2.2 (23-29)

Range of MCD of individual potential pairs

11-69

15-64

12-45

No. of abnormal SFEMG tests

1/6 (16.6%)

5/6 (83%)

0/6 (0%)

Table 1. Results of single-fibre electromyography (SFEMG) studies in the study groups

SD – standard deviation, MCD – mean of differences between intervals between consecutive potential pairs

0

5

10

15

20

25

30

35

40

45

50

Patients

MCD

o

f i

nd

ivi

dual

po

te

nt

ial

pairs

[μ

s]

Fig. 1. Results of mean of differences between intervals between individual
consecutive potential pairs (MCD) in patients with cluster headache, migraine
with aura and control group

80

70

60

50

40

30

20

10

0

cluster headache

migraine with aura

control group

Izabela Domitrz, Ma³gorzata Gawe³, Wojciech Domitrz, Anna Kostera-Pruszczyk, Hubert Kwieciñski

Neurologia i Neurochirurgia Polska 2012; 46, 2

143

of cluster headache is currently unknown. The first
hypothesis was based on the neurovascular theory. In
cluster headache, activation of the trigemino-vascular
system is present, but it is not established whether this
is a cause or consequence of cluster headache. The para -
sympathetic activation is thought to be mediated by
a trigemino-autonomic reflex in the brainstem circuitry
via the seventh cranial nerve. However, we examined
the motor part of the trigeminal-facial circuitry by blink-
reflex interictally and we did not reveal any abnormali-
ties in cluster headache patients. Raudino tested the elec-
trically elicited blink reflex during a symptomatic period
in patients with cluster headache. In nearly all cases
(11/12), the amplitude of the contralateral R2 response
on the symptomatic side was significantly lower [16].
In our 3 patients with cluster headache, blink reflex did
not reveal any differences between the symptomatic and
asymptomatic side.

On the other hand, the activation of the posterior

hypothalamus during attacks probably plays a role in
cluster headache. Also, more studies have recently been
done on polymorphism of the HCRTR2 gene (hypocre-
tin receptor 2), which could be a susceptibility gene in
cluster headache. Hypocretin is secreted by the hypo-
thalamus activated in cluster headache [17].

The absence of neurotransmitter dysfunction in clus-

ter headache could be explained by a different mecha-
nism and lack of pathology of ion channels identified in
migraine with aura.

The SFEMG abnormalities present in our mi -

graineurs were mild. They were manifested as a shift of
individual MCD values towards the upper limit of nor-
mal. Although in a few potential pairs the MCD values
exceeded 55 μs, there was no blocking. Such findings
could be interpreted as a mild, yet generalized reduc-
tion in the safety factor of the neuromuscular junction.
Neuromuscular transmission abnormalities were report-
ed by Ambrosini et al. [13], who studied NMT in pa -
tients with migraine with stimulated SFEMG, observ-
ing prolonged jitter and blocking. Recently, three
patients were described with episodic ataxia type 2,
in whom the mean MCD values fell between 40 and
59 μs, with maximal jitter values up to 214 μs, reaching
the degree of abnormalities observed in myasthenic
patients [18]. Therefore, the blinded setting of the
SFEMG is recommended for studying migraine
patients, as it decreases the possible observation bias.
Single-fibre electromyography with voluntary activation,
as employed in our study, excludes the risk of sub-
threshold stimulation as the cause of increased jitter or

axonal blocking when the SFEMG is studied with
axonal stimulation [19].

The fact that SFEMG abnormalities were limited

to patients with migraine with aura may be an addition-
al argument supporting the opinion that migraine and
cluster headache are completely distinct disorders, and
the cluster headache group may be heterogeneous group
with different pathogenesis.

Disclosure

Authors report no conflict of interest.

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Izabela Domitrz, Ma³gorzata Gawe³, Wojciech Domitrz, Anna Kostera-Pruszczyk, Hubert Kwieciñski